PROJECT SUMMARY The quality of life of over half a million surviving head-and-neck cancer patients is drastically decreased due to co-irradiation of healthy saliva-secreting salivary glands. Current treatment of irradiation-induced xerostomia, a condition that results in hyposalivation or dry mouth, is limited. Therapies are largely ineffective or solely provide temporary relief; enforcing the need to implement new treatments to long-term restore hyposalivation. Only a few strategies to date have been proposed and validated in vivo. In a mouse model, successful long- term repair of irradiated salivary glands was obtained by a surgical intra-glandular injection of stem cells. For human patients, we propose to deliver cells via a non-surgical retrograde ductal infusion. In this procedure, cells are directly infused into salivary glands through the main duct that drains saliva into the oral cavity. Here, we initiate the technical translation of stem cell transplantation to regenerate irradiated salivary glands. Based on existing evidence using this technique in a higher animal model, we determined that additional efforts are necessary to consistently deliver a large number of cells into the parenchyma of irradiated glands. We hypothesize that mechanical forces aid in breaching the epithelial lining of the parenchyma. To test this, various pressure-related conditions will be used to efficiently and locally deliver cells into the tissue. These studies will facilitate successful delivery of stem cells into irradiated glands, and expedite the clinical translation of stem cell-based transplantations to repair xerostomia in surviving head-and-neck cancer patients.